Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Summary of the safety profile
Sedation of adult ICU (Intensive Care Unit) patients
The most frequently reported adverse reactions with dexmedetomidine in ICU setting are hypotension, hypertension and bradycardia, occurring in approximately 25%, 15% and 13% of patients respectively.
Hypotension and bradycardia were also the most frequent dexmedetomidine-related serious adverse reactions occurring in 1.7% and 0.9% of randomised Intensive Care Unit (ICU) patients respectively.

Procedural/awake sedation
The most frequently reported adverse reactions with dexmedetomidine in procedural sedation are listed below (the protocols of phase III studies contained pre-defined thresholds for reporting changes in blood pressure, respiratory rate and heart rate as AEs):
-      Hypotension (55% in dexmedetomidine-group vs. 30% in placebo-group receiving rescue midazolam and fentanyl)
-      Respiratory depression ( 38% in dexmedetomidine-group vs. 35% in placebo-group receiving rescue midazolam and fentanyl)
-      Bradycardia (14% in dexmedetomidine-group vs. 4% in placebo-group receiving rescue midazolam and fentanyl)

Tabulated list of adverse reactions
The adverse reactions listed in Table 1 have been accumulated from pooled data of clinical trials in intensive care.
Adverse reactions are ranked under headings of frequency, the most frequent first, using the following convention: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000), very rare (<1/10,000).

Table 1. Adverse reactions

Metabolism and nutrition disorders
Common:        Hyperglycaemia, hypoglycaemia
Uncommon:      Metabolic acidosis, hypoalbuminaemia
Psychiatric disorders
Common:          Agitation
Uncommon:        Hallucination

Cardiac disorders
Very common: Bradycardia1,2
Common:         Myocardial ischaemia or infarction, tachycardia
Uncommon:       Atrioventricular block1, cardiac output decreased, cardiac arrest1 
Vascular disorders
Very common: Hypotension1,2, hypertension1,2

Respiratory, thoracic and mediastinal disorders
Very сommon: Respiratory depression2,3
Uncommon:        Dyspnoea, apnoea
Gastrointestinal disorders
Common:          Nausea2, vomiting, dry mouth2
Uncommon:        Abdominal distension
Renal and urinary disorders
Not known:      Polyuria

General disorders and administration site conditions
Common:         Withdrawal syndrome, hyperthermia
Uncommon: Drug ineffective, thirst
1
See section on Description of selected adverse reactions
2
Adverse reaction observed also in procedural sedation studies
3
Incidence ‘common’ in ICU sedation studies

Description of selected adverse reactions
Clinically significant hypotension or bradycardia should be treated as described in section 4.4.
In relatively healthy non-ICU subjects treated with dexmedetomidine, bradycardia has occasionally led to sinus arrest or pause. The symptoms responded to leg raising and anticholinergics such as atropine or glycopyrrolate. In isolated cases bradycardia has progressed to periods of asystole in patients with pre-existing bradycardia. Also cases of cardiac arrest, often preceded by bradycardia or atrioventricular block, have been reported.

Hypertension has been associated with the use of a loading dose and this reaction can be reduced by avoiding such a loading dose or reducing the infusion rate or size of the loading dose.

Paediatric population
Children > 1 month post-natal, predominantly post-operative, have been evaluated for treatment up to 24 hours in the ICU and demonstrated a similar safety profile as in adults. Data in new-born infants
(28 – 44 weeks gestation) is very limited and restricted to maintenance doses ≤ 0.2 mcg/kg/h. A single case of hypothermic bradycardia in a neonate has been reported in the literature.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form: www.sideeffects.health.co.il